Citations

AbstractObjectivesRadiocontrast nephropathy (RCN) is a known complication of procedures in which intravascular iodinated contrast material is used. The authors sought to determine the risk factors for RCN after emergency department (ED) contrast‐enhanced computerized tomography (CECT).MethodsThis was a retrospective case–control study of patients presenting to a tertiary care ED between January 1, 2004, and December 31, 2006. Inclusion criteria were CECT performed in the ED, serum creatinine measured prior to CECT, and serum creatinine measured 48 to 96 hours after CECT. Exclusion criterion was dialysis‐dependent renal failure prior to CECT. The outcome of RCN was defined as an absolute creatinine increase of greater than or equal to 0.5 mg/dL, or a 25% increase above baseline. The charts of all RCN patients and a random sample of non‐RCN patients were reviewed to document the presence or absence of potential risk factors. Univariate analysis was performed using chi‐square and multiple logistic regression applying a weighted technique to account for sampling of non‐RCN patients.ResultsAmong the 5,006 patients meeting inclusion criteria, 349 (7%) developed RCN. Multiple regression analysis demonstrated that serum creatinine > 2 mg/dL, liver disease, heart failure, hematocrit < 30%, hypertension, and diabetes were risk factors for RCN, whereas age > 75 years, vascular disease, and serum creatinine > 1.5 mg/dL were not. The area under the curve (AUC) for the model was 0.65. Although the risk of RCN increased with the number of risk factors present, we could not develop a model with sufficient diagnostic accuracy to guide clinical decision‐making.ConclusionsThe authors report risk factors for RCN in a large case–control study, but could not develop an accurate decision tool to identify patients at increased risk for RCN after ED CECT.

Abstract Cancer-associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAFs are “activated” and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma as a desmoplastic tumor model, we investigated the sensitivity of liver CAFs to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells but lacked similar effects in quiescent fibroblasts or cholangiocarcinoma cells. Unlike cholangiocarcinoma cells, neither CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAFs or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAFs appeared to be due, in part, to upregulation of the proapoptotic protein Bax. Short hairpin RNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors, and apoptotic cell death. In a syngeneic rat model of cholangiocarcinoma, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth, and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAFs in the tumor microenvironment as a general strategy to attack solid tumors. Cancer Res; 73(2); 897–907. ©2012 AACR.

Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD+ metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD+ levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD+ase in mammals. Moreover, CD38 knockout mice have higher NAD+ levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD+ levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD+ levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD+ levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD+-dependent pathways.